rs56034831

Variant names:

• chr2-178632406-C-T
• rs56034831
• NM_001267550.2:c.43488G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.43488G>A​(p.Arg14496Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,581,932 control chromosomes in the GnomAD database, including 616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (58 hom., cov: 32)
  • Exomes 𝑓: 0.026 (558 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: -0.188
• Publications: 3 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-178632406-C-T is Benign according to our data. Variant chr2-178632406-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.188 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0202 (3070/151854) while in subpopulation NFE AF = 0.0315 (2142/67936). AF 95% confidence interval is 0.0304. There are 58 homozygotes in GnomAd4. There are 1473 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.43488G>A	p.Arg14496Arg	synonymous	Exon 236 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.38565G>A	p.Arg12855Arg	synonymous	Exon 186 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.35784G>A	p.Arg11928Arg	synonymous	Exon 185 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.43488G>A	p.Arg14496Arg	synonymous	Exon 236 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.43332G>A	p.Arg14444Arg	synonymous	Exon 234 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.43212G>A	p.Arg14404Arg	synonymous	Exon 234 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3071 AN: 151736 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00574

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0199 AC: 4273 AN: 215102 AF XY: 0.0202

Gnomad AFR exome AF: 0.00430

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.0267

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0355

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0265 AC: 37839 AN: 1430078 Hom.: 558 Cov.: 32 AF XY: 0.0258 AC XY: 18246 AN XY: 708450

African (AFR) AF: 0.00432 AC: 138 AN: 31920

American (AMR) AF: 0.00690 AC: 262 AN: 37948

Ashkenazi Jewish (ASJ) AF: 0.0290 AC: 724 AN: 24962

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39016

South Asian (SAS) AF: 0.000301 AC: 24 AN: 79818

European-Finnish (FIN) AF: 0.0336 AC: 1768 AN: 52620

Middle Eastern (MID) AF: 0.00409 AC: 23 AN: 5630

European-Non Finnish (NFE) AF: 0.0305 AC: 33507 AN: 1099102

Other (OTH) AF: 0.0236 AC: 1392 AN: 59062

GnomAD4 genome AF: 0.0202 AC: 3070 AN: 151854 Hom.: 58 Cov.: 32 AF XY: 0.0199 AC XY: 1473 AN XY: 74196

African (AFR) AF: 0.00572 AC: 237 AN: 41414

American (AMR) AF: 0.0112 AC: 171 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4798

European-Finnish (FIN) AF: 0.0367 AC: 387 AN: 10552

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2142 AN: 67936

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

Alfa AF: 0.0291 Hom.: 147

Bravo AF: 0.0173

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.43
DANN	Benign	0.49
PhyloP100		-0.19
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56034831; hg19: chr2-179497133;